The long-term goal of the proposed research is to identify mechanisms responsible for the effects of growth hormone (GH) signaling on aging and longevity in mammals. Studies conducted by the applicants during the last 10 years, together with results obtained in other laboratories, have provided unequivocal evidence that GH deficiency and GH insensitivity in mice are associated with a marked increase in mean and maximal longevity. Studies of age-sensitive traits and analysis of survival characteristics in GH-deficient and GH-resistant mice indicate that increased longevity of these animals is coupled with and most likely due to a delay and/or deceleration of the process of biological aging. Our collaborative studies and work of other investigators defined a series of mechanisms that might, in principle, link GH signaling with longevity. In the proposed work we will use both well-characterized and novel mouse mutants to probe several of these specific mechanisms. Our aim is to develop a compelling model of the pathway or pathways that connect diminished GH or IGF-I signaling to extended longevity and to relate these pathways to maintenance of cognitive and physical function. The proposed collaborative studies will define the role of liver, adipose tissue and muscle in mediating the effects of GH and IGF-I on age-sensitive traits and longevity; and to elucidate the interactive effects of altered insulin signaling, adipocyte secretory profiles and stress resistance in mediating these effects. Project 1 will relate somatotropic and insulin signaling to stress resistance and aging. Project 2 will produce novel animals lacking the GHR/GHBP gene only in the liver, white adipose tissue or muscle. Project 3 will study mechanisms of stress resistance in fibroblasts and pre-adipocytes and evaluate longevity and age-sensitive traits in novel mutant mice developed in Project 2. Project 4 will characterize pre-adipocyte utilization, characteristics and senescence in mutants with altered GH signaling. Core A will coordinate research, information exchange and communication with Advisory Committee, develop shared data base and provide statistical support. Core B will assess gross and microscopic pathological changes with emphasis on novel mutants developed by Project 2. Improved understanding of the role of somatotropic and insulin signaling in the control of mammalian aging is needed for designing lifestyle and pharmacological interventions to maintain health and functionality during human aging. This information is also needed to develop rational basis for exploring or discouraging the use of human GH as an anti-aging agent.